N-alkylaspartyl dipeptide ester compounds

ABSTRACT

The present invention provides N-alkylaspartyl dipeptideester compounds and salts thereof, such as N-[N-[3-(3-hydroxy-4-methoxyphenyl)-3-methylbutyl]-L-α-aspartyl]-L-phenylalanine 1-methyl ester, which provide high degrees of sweetness in comparison to conventional products, compositions and products containing the novel aspartyl dipeptide ester compounds and method of producing the novel aspartyl dipeptide ester compounds.

This application is a Continuation International Application No.PCT/JP99/04977 Filed on Sep. 10, 1999.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention relates to a novel N-alkylaspartyl dipeptide estercompounds, a sweetening agent or a sweetened food or similar productscomprising the compound as an effective component. The invention furtherprovides methods of imparting sweetness in a product and methods ofmaking the N-alkylaspartyl dipeptide ester compounds.

2. Discussion of the Background

In recent years, as eating habits and products eaten have changed,fatness caused by excessive sugar intake and diseases caused by fatnesshave been of significant concern. Accordingly, the development of alow-calory sweetener (sweetening agent) that replaces sugar has been indemand. A sweetener that has been widely used is aspartame which isexcellent in safety, quality of sweetness and taste properties. However,there are problems with aspartame with respect to its stability. WO94/11391 states that compounds in which an alkyl group is introduced ona nitrogen atom of aspartic acid in the aspartame markedly improves thesweetening potency and also results in a slight improvement in thestability of the compound. The best compound described in WO 94/11391 isN-[N-(3,3-dimethylbutyl)-L-α-aspartyl]-L-phenylalanine 1-methyl esterhaving a 3,3-dimethylbutyl group as an alkyl group and which has asweetening potency of 10,000 times that of sucrose (the value isobtained by comparing the compound to 2%, 5% and 10% sucrose solutions).

Aspartame compounds having 20 different substituents other than the3,3-dimethylbutyl group are also disclosed where the compounds havesweetening potencies less than 2,500 times that of sucrose. Compoundshaving a 3-(substituted phenyl) propyl group as an alkyl group are alsoshown. Among these, N-[N-(3-phenylpropyl)-L-(α-aspartyl]-L-phenylalanine1-methyl ester andN-[N-(3-(3-methoxy-4-hydroxyphenylpropyl)-L-α-aspartyl]-L-phenylalanine1-methyl ester are described as having sweetening potencies of 1500 and2500 times that of sucrose, respectively. These sweetening potencies arefar less than that ofN-[N-(3,3-dimethylbutyl)-L-α-aspartyl]-L-phenylalanine 1-methyl ester,which is 10,000 times that of sucrose. Further described areN-[N-[(RS)-3-phenylbutyl]-L-(α-aspartyl]-L-phenylalanine 1-methylester,which has as an alkyl group a 3-phenyl propyl group to the thirdposition of which a methyl group is introduced, that is a 3-phenyl butylgroup, is reported to have a sweetening potency of 1,200 times that ofsucrose. The N-[N-(3-phenylpropyl)-L-α-aspartyl]-L-phenylalanine1-methyl ester has a lower sweetening potency due to the methyl groupintroduced at the third position.

Furthermore,N-[N-[3-(3-methoxy-4-hydroxyphenyl)(RS)-1-methylpropyl]-L-α-aspartyl]-L-phenylalanine1-methylester, having a structure corresponding toN-[N[3-(3-methoxy-4-hydroxyphenyl)propyl)-L-(α-aspartyl]-L-phenylalanine 1-methyl ester, with a methylgroup on the first position of the propyl group is reported to have asweetening potency of 500 times that of sucrose. The significantly lowersweetening potency is due to the methyl group on the the propyl group.

Another example of replacing the L-phenylalanine methyl ester moietywith another amino acid ester isN-[N-(3,3-dimethylbutyl)-L-α-aspartyl]-L-tyrosine 1-methyl ester whichhas a sweetening potency of 4,000 times that of sucrose.

In view of the foregoing, development of a low-calory sweetener having asuperior sweetening potency is in demand.

Thus, the present inventors sought to solve the long-standing problemsassociated with prior low-calory sweeteners and provide novelN-alkylaspartyl dipeptide ester compounds which are excellent in safetyand which have sweetening potencies equal to or higher than that ofN-[N-(3,3-dimethylbutyl]-L-α-aspartyl]-L phenylalanine 1-methylester,and a low-calory sweetening agent comprising the compound as aneffective component.

SUMMARY OF THE INVENTION

Accordingly, one object of the present invention is an N-alkylaspartyldipeptide ester compound, and salts thereof, represented by formula (1):

wherein R₁, R₂, R₃, R₄ and R₅ are independent from each other, selectedfrom the group consisting of a hydrogen atom, a hydroxyl group, analkoxy group having 1 to 3 carbon atoms, an alkyl group having 1 to 3carbon atoms and a hydroxy alkyloxy group having two or three carbonatoms, and R₁ and R₂, or R₂ and R₃, optionally, form a methylene dioxygroup, and R₄ and R₅ , and R₁ or R₃ which do not form the methylenedioxy group are defined as above;

R₆, R₇, R₈, R₉ and R₁₀ are independent from each other, a hydrogen atomor an alkyl group with 1 to 3 carbon atoms; and optionally, two of R₆,R₇, R₈, R₉ and R₁₀ may combine to form an alkylene group with 1 to 5carbon atoms, and R₆, R₇, R₈, R₉ and R₁₀ which do not form the alkylenegroup with 1 to 5 carbon atoms are defined as above;

R₁₁ is selected from the group consisting of a hydrogen atom, a benzylgroup, a p-hydroxy benzyl group, a cyclohexyl methyl group, a phenylgroup, a cyclohexyl group, a phenyl ethyl group and a cyclohexyl ethylgroup;

R₁₂ is selected from the group consisting of a hydrogen atom and analkyl group with 1 to 3 carbon atoms; and

R₁₃ is selected from the group consisting of alkyl groups with 1 to 4carbon atoms;

with the proviso that the following are excluded:

where R₆, R₇, R₈, R₉ and R₁₀ are a hydrogen atom at the same time,

where R₆ is a methyl group, R₁, R₂, R₃, R₄, R₅, R₇, R₈, R₉, R₁₀ and R₁₂are a hydrogen atom at the same time and R₁₁ is a benzyl group or ap-hydroxy benzyl group, at the same time; and

where R₂ or R₄ is a methoxy group, R₃ is a hydroxyl group, R₁₀ is amethyl group, R₁, R₄ or R₂, R₅ , R₆, R₇, R₈ and R₉ are hydrogen atoms atthe same time, and R₁₁ is a benzyl group or a p-hydroxy benzyl group.

Other objects of the present inventions include compositions comprisingthe N-alkylaspartyl dipeptide ester compound, methods of impartingsweetness into a substance by adding the N-alkylaspartyl dipeptide estercompound to the substance and methods of making the N-alkylaspartyldipeptide ester compound.

DETAILED DESCRIPTION OF THE INVENTION

Each document, patent application or patent publication cited by orreferred to in this disclosure is incorporated by reference in itsentirety.

For resolving the above problem, the present inventors have synthesizeda variety of compounds in which a variety of 3-(substituted phenyl)propyl group, such as 3,3-dialkyl-3-(substituted phenyl) propyl groupsor (RS)-3-alkyl-3-(substituted phenyl) propyl groups, have beenintroduced on a nitrogen atom of an aspartic acid constituting anaspartame and an aspartame compound, by reductive alkylation, using a3-phenylpropionaldehyde compound, a cinnamaldehyde compound, a(2-phenylethyl) alkyl ketone compound or the like having a variety ofsubstituents on a phenyl group and also having 1 to 4 alkyl substituentson the main chain, and examined the sweetening potency of thesecompounds. The compound corresponds to the aspartame the L-phenylalaninemethyl ester moiety of which is substituted by another amino acid estertherein. As a result of our investigations, the sweetening potency ofsome of the aspartame compounds is much higher in sweetening potencythan N-[N-(3,3-dimethylbutyl)-L-α-aspartyl]-L-phenylalanine1-methylester reported to have the sweetening potency of 10000 timesthat of sucrose, to say nothing ofN-[N-[(RS)-3-phenylbutyl]-L-(α-aspartyl]-L-phenylalanine 1-methylesterreported to have the sweetening potency of 1200 times that of sucrose orN-[N-(3,3-dimethylbutyl)-L-α-aspartyl]-L-tyrosine 1-methylester reportedto have a sweetening potency equal to 4000 times that of sucrose, asdisclosed in the international Patent Publication WO 94/11391, and that,in particular, the compound represented by the general formula (1) belowis superior as a sweetening agent.

The novel N-alkylaspartyl dipeptide ester compound according to thepresent invention includes compounds represented by the above formula(1) and salts thereof. Preferably, the amino acids in the compound offormula (1), aspartic acid, is in the L-isomer. Other amino acids may bein the L- or D-isomer, as desired.

In the compounds of the present invention substituents are defined asknown in the art and include a hydrogen atom (H), a hydroxyl group (OH),an alkoxy group with 1 to 3 carbon atoms (OCH₃, OCH₂CH₃, OCH₂CH₂CH₃,etc.), an alkyl group with 1 to 3 carbon atoms (CH₃, CH₂CH₃, CH₂CH₂CH₃,etc.), a hydroxy alkyloxy group with two or three carbon atoms(O(CH₂)2OH, OCH₂CH (OH) CH₃, etc.), a methylene dioxy group (OCH₂O) andan alkylene group with 1 to 5 carbon atoms (such as CH₂, CH₂CH₂,CH₂CH₂CH₂ and so forth).

Preferred substituents in the compounds of formula (1) include:

(1) R₆ is a methyl group.

(2) R₇ is a methyl group.

(3) R₈, R₉ and R₁₀ are hydrogen atoms.

(4) R₁₀ is a methyl group.

(5) R₆ and R₇ combine to form an alkylene group having 1 to 5 carbonatoms.

(6) Above compounds (1), not containing the compounds wherein R₁, R₂,R₃, R₄ and R₅ are hydrogen atoms.

(7) R₆ is a methyl group and R₁, R₂, R₃, R₄, R₅, R₇, R₈, R₉ and R₁₀ arehydrogen atoms.

(8) R₆ is an alkyl group having two or three carbon atoms.

(9) Two of R₆, R₇, R₈, R₉ and R₁₀ combined to form an alkylene groupwith one to five carbon atoms.

(10) R₆, R₇, R₈, R₉ are hydrogen atoms, R₁₀ is a methyl group, R₂ is ahydrogen atom; a hydroxyl group; an alkoxy group with two or threecarbon atoms, an alkyl group with one to three carbon atoms, a hydroxyalkyloxy group having two or three carbon atoms; or R₂ combined with R₁or R₃ is a methylene dioxy group.

(11) R₆, R₇, R₈ and R₉ are hydrogen atoms, R₁₀ is a methyl group, R₃ isa hydrogen atom, an alkoxy group with one to three carbon atom, an alkylgroup with one to three carbon atoms and a hydroxy alkyloxy group havingtwo or three carbon atoms; and R₂ may combine with R₁ or R₃ form amethylene dioxy group.

(12) R₁, R₄, R₅, R₆, R₇, R₈ and R₉ are hydrogen atoms, R₁₀ is a methylgroup, R₂ is a methoxy group, R₃ is a hydroxyl group, and R₁₁ is ahydrogen atom, a cyclohexyl methyl group, a phenyl group, a cyclohexylgroup, a phenylethyl (CH₂CH₂C₆H₅) and a cyclohexylethyl group(CH₂CH₂C₆H₁₁).

(13) R₆ and R₇, are hydrogen atoms and R₁₀ is an alkyl group with two orthree carbon atoms.

(14) R₆ and R₇ are hydrogen atoms and two of R₈, R₉ and R₁₀ may combineto form an alkylene group with 1 to 5 carbon atoms.

(15) R₆, R₇ and R₁₀ are hydrogen atoms, at least one of R₈ and R₉ is analkyl group with one to three carbon atoms or R₈ and R₉ combine to forman alkylene group with 1 to 5 carbon atoms.

(16) R₃ is a methoxy group, R₁, R₂, R₄, R₅, R₇, R₈, R₉, R₁₀ and R₁₂ arehydrogen atoms, R₆ and R₁₃ are a methyl groups and R₁₁ is a benzylgroup.

(17) R₂ is a hydroxyl group, R₁, R₃, R₄, R₅, R₇, R₈, R₉, R₁₀ and R₁₂ arehydrogen atoms, R₆ and R₁₃ is a methyl group, and R₁₁ is a benzyl group.

(18) R₂ is a methoxy group, R₃ is a hydroxyl group, R₁, R₄, R₅, R₇, R₈,R₉, R₁₀ and R₁₂ are hydrogen atoms, R₆ and R₁₃ are methyl groups and R₁₁is a benzyl group.

(19) R₂ is a hydroxyl group, R₃ is a methoxy group, R₁, R₄, R₅, R₇, R₈,R₉, R₁₀ and R₁₂ are hydrogen atoms, R₆ and R₁₃ are methyl groups and R₁₁is a benzyl group.

(20) R₂ is a methoxy group, R₃ is a hydroxyl group, R₁, R₄, R₅, R₇, R₈,R₉, R₁₀ and R₁₂ are hydrogen atoms, R₆ and R₁₃ are methyl groups and R₁₁is a p-hydroxybenzyl group.

(21) R₂ is a hydroxyl group, R₃ is a methoxy group, R₁, R₄, R₅, R₇, R₈,R₉ , R₁₀ and R₁₂ is a hydrogen atom, R₆ and R₁₃ are methyl groups andR₁₁ is a cyclohexylmethyl group.

(22) R₃ is a methoxy group, R₁, R₂, R₄, R₅, R₈, R₉, R₁₀ and R₁₂ arehydrogen atoms, R₆, R₇ and R₁₃ are a methyl groups, and R₁₁ is a benzylgroup.

(23) R₃ is a hydroxyl group, R₁, R₂, R₄, R₅, R₈, R₉ , R₁₀ and R₁₂ arehydrogen atoms, R₆, R₇ and R₁₃ are methyl groups and R₁₁ is a benzylgroup.

(24) R₂ is a methoxy group, R₃ is a hydroxyl group, R₁, R₄, R₅, R₈, R₉,R₁₀ and R₁₂ are hydrogen groups, R₆, R₇ and R₁₃ are methyl group sandR₁₁ is a benzyl group.

(25) R₂ is a hydroxyl group, R₃ is a methoxy group, R₁, R₄, R₅, R₈, R₉,R₁₀ and R₁₂ are hydrogen groups, R₆, R₇ and R₁₃ are methyl groups andR₁₁is a benzyl group.

(26) R₂ is a methyl group, R₃ is a hydroxyl group, R₁, R₄, R₅, R₇, R₈,R₉, R₁₀ and R₁₂ are hydrogen atoms, R₆ and R₁₃ are methyl groups and R₁₁is a benzyl group.

(27) R₂ is a hydroxyl group, R₃ is a methoxy group, R₁, R₄, R₅, R₆, R₇,R₉, R₁₀ and R₁₂ are hydrogen atoms, R₈ and R₁₃ are methyl groups and R₁₁is a benzyl group.

(28) R₁ is a hydroxyl group, R₂, R₃, R₄, R₅, R₈, R₉, R₁₀ and R₁₂ arehydrogen atoms, R₆, R₇ and R₁₃ are methyl groups and R₁₁ is a benzylgroup.

(29) R₁ is a hydroxyl group, R₃ is a methoxy group, R₂, R₄, R₅, R₈, R₉,R₁₀ and R₁₂ are hydrogen atoms, R₆, R₇ and R₁₃ are methyl groups and R₁₁is a benzyl group.

(30) R₁ is a hydroxyl group, R₃ is a methyl group, R₂, R₄, R₅, R₆, R₉,R₁₀ R₁₀ and R₁₂ are hydrogen atoms, R₆, R₇ and R₁₃ are methyl groups andR₁₁ is a benzyl group.

(31) R₂ and R₃ combine to form a methylene dioxy group, R₁, R₄, R₅, R₈,R₉, R₁₀ and R₁₂ are hydrogen atoms, R₆, R₇ and R₁₃ are methyl groups andR₁₁ is a benzyl group.

(32) R₂ is a methyl group, R₃ is a methoxy group, R₁, R₄, R₅, R₈, R₉,R₁₀ and R₁₂ are hydrogen atoms, R₆, R₇ and R₁₃ are methyl groups and R₁₁is a benzyl group.

(33) R₂ is a methyl group, R₃ is a hydroxyl group, R₁, R₄, R₅, R₈, R₉,R₁₀ and R₁₂ are are hydrogen atoms, R₆, R₇ and R₁₃ are methyl groups,and R₁₁ is a benzyl group.

(34) R₂ is a hydroxyl group, R₃ is a methyl group, R₁, R₄, R₅, R₈, R₉,R₁₀ and R₁₂ are hydrogen atoms, R₆, R₇ and R₁₃ are methyl groups and R₁₁is a benzyl group.

(35) R₂ is a methoxy group, R₃ is a hydroxyl group, R₁, R₄, R₅, R₈, R₉,R₁₀ and R₁₂ are hydrogen groups, R₆ and R₇ combine to form atetramethylene group, R₁₁ is a benzyl group and R₁₃ is a methyl group.

(36) R₂ is a hydroxyl group, R₃ is a methoxy group, R₁, R₄, R₅, R₈, R₉,R₁₀ and R₁₂ are hydrogen atoms, R₆ and R₇ are methyl groups, R₁₁ is abenzyl group and R₁₃ is an ethyl group.

(37) R₂ and R₃ are hydroxyl groups, R₁, R₄, R₅, R₈, R₉, R₁₀ and R₁₂ arehydrogen atoms, R₆, R₇ and R₁₃ are methyl groups, and R₁₁ is a benzylgroup.

(38) R₂ is a hydroxyl group, R₃ is a methoxy group, R₁, R₄, R₅, R₈, R₉and R₁₀ are hydrogen atoms, R₆, R₇, R₁₂ and R₁₃ are methyl groups andR₁₁ is a benzyl group.

(39) In the compounds of formula (1), particularly with substituentslisted in (16) through (21) and (26) the carbon atom to which R₈ islinked is in the (R), (S), (RS) configuration or the like.

(40) In the compounds of formula (1), particularly with substituentslisted in (27) the carbon atom to which is R₈ linked in the formula isin the (R), (S), (RS) configuration or the like.

(41) The carbon atom to which R₁₀ is linked in the formula (1) is in the(R), (S), (RS) configuration or the like.

Compositions according to the present invention contain one or more ofthe compounds of formula (1). When the compounds (including compounds inthe present invention and the salts thereof) of the present inventionare used as sweeteners, these may of course be used in combination withother sweeteners as desired or needed.

Additional embodiments of the present invention include compositionscontaining the compound of formula (1) where such compositions containadditives, stabilizers, carriers and the like which are commonly used inthe art.

When the compounds of the present invention are used as sweeteners, anappropriate carrier and/or an appropriate bulking agent may be used asrequired. For example, a carrier, a bulking agent or the like which isknown in the art and so far used for the sweeteners is available. Theappropriate carriers or bulking agent may be selected from polydextrose,starch, maltodextrines, cellulose, methylcellulose,carboxymethylcellulose and other cellulose compounds, sodium alginate,pectins, gums, lactose, maltose, glucose, sucrose, leucine, glycerole,mannitol, sorbitol, xylitol, erythritol, and equivalents thereof.

The compounds of the present invention can be used as sweeteners oringredients therefor, and further as sweeteners for products such asfoods, beverages and the like to which a sweetness has to be imparted.Examples of such products include soft-drinks, fruit juices, teas,water, confectioneries, chewing gum, hygiene products, toiletries,cosmetics, pharmaceutical products and veterinary products for animals.Still further, they can be used as a form of products having sweetnessincluding the compounds of the present invention and they can be used ina method of imparting sweetness to the products requiring sweetness. Themethod therefor can be, known methods for example, conventional methodsfor using a sweetening ingredient for a sweetener in the sweeteners orthe method of imparting sweetness. Accordingly, a preferred embodimentof the present invention is a method of imparting sweetness in asubstance or a product by adding one or more of the compounds of formula(1) to said substance or product. Such substances or products includethose described above.

The compound of formula (1), where R₁₀ is a hydrogen atom, can beprepared by reacting under reductive alkylation conditions an aldehydehaving the formula (2):

where R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₈ and R₉ have the same meaning as R₁,R₂, R₃, R₄, R₅, R₆, R₇, R₈ and R₉, respectively in the above formula(1); and if R₆ and R₇, or R₈ and R₉ are not the same substituents, thereis no particular limitation to the configuration of carbon atoms towhich R₆ and R₇, or R₈ and R₉ are linked, such that it may be (R), (S),(RS) or the like whichever is desired;

with an aspartame compound shown by the following general formula (3):

wherein R₁₁, R₁₂ and R₁₃ in the above formula (3) have the same meaningas R₁₁, R₁₂ and R₁₃, respectively in the above formula (1), R₁4 denotesa hydrogen atom or a substituent that can be converted into a hydrogenatom under the reductive alkylation condition and R₁₅ denotes a hydrogenatom, a benzyl group or a substituent that may be used for protecting acarboxyl group such as a t-butyl group or the like.

The compound of formula (1), where R₇, R₉ and R₁₀ are hydrogen atoms canbe prepared by reacting under reductive alkylating conditions, analdehyde having the formula (4)

where R₁, R₂, R₃, R₄, R₅, R₆ and R₈ have the same meaning as R₁, R₂, R₃,R₄, R₅, R₆ and R₈, respectively in the above formula (1);

with an aspartame compound shown by the above-mentioned general formula(3).

The compound of formula (1) where R₁₀ is a hydrogen atom, can beprepared by reacting under reductive alkylating conditions, an aldehydehaving formula (5):

where R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₈, R₉ and R₁₀ have the same meaningsas R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₈, R₉ and R₁₀, respectively in formula(1);

it being noted that, if R₆ and, R₇, or R₈ and R₉ are not the samesubstituents, there is no particular limitation to the configuration ofthe carbon atoms to which R₆ and R₇, or R₈ and R₉ are linked, such thatit may be (R), (S), (RS) or the like whichever is desired;

with the aspartame compound shown by the above general formula (3).

The aforementioned methods of preparing the compounds of formula (1)include a reacting step under the reductive alkylation conditions, andmay also include other reactive steps. An additional step or steps maybe included, following the reacting step under the reductive alkylationcondition, for example, de-protection in a hydroxyl group or the otherfunctional group and/or a salt forming step or the like. Such methods ofprotection and deprotection can be performed as described in T. W.Greene and P. G. M. Wuts, “Protective Groups in Organic Synthesis”, JohnWiley and Sons, Inc. (1999).

As the substituent that can be converted into a hydrogen atom under thereductive alkylation condition, those that are known in the art whichcan be used for such purpose, e.g., benzyloxy carbonyl group or thelike, may be optionally selected depending on the particular reductivealkylation conditions employed in the reaction. As these reductivealkylation conditions, the conditions as known in the art, or anysuitable conditions that will be developed in future, such as acondition employing metal hydrides, may be used, as needed.

Additional embodiments of the present invention, if aldehydes shown bythe general formulas (2), (4) or (5) include hydroxyl groups, theaforementioned preparation methods may employ an aldehyde, the hydroxylgroup of which is protected by a suitable protecting group, such asbenzyl group.

Salts of the compounds of the present invention include, for example,salts of alkali metals such as sodium and potassium, salts of alkaliearth metals, such as calcium and magnesium, ammonium salt with ammonia,salts with amino acids, such as lysine and arginine, salts withinorganic acids, such as hydrogen chloride and sulfuric acid, salts withorganic acids, such as citric acid and acetic acid, and salts withsweetening agents, such as saccharin, acesulfame, cyclamic acid andglycyrrhizic acid. The preparation of the salts of the present compoundof formula(1) can be prepared as known in the art.

The N-alkylaspartyl dipeptide ester compound of the present inventioncan be synthesized by reductive alkylation of aspartame or aspartamecompounds, that is compounds obtained by replacing an L-phenylalaninemethylester moiety in the aspartame by another amino acid ester, using a3-phenylpropionaldehyde compound, a cinnamaldehyde compound or a(2-phenylethyl) alkylketone compound, which has different substituentson a phenyl group and also having one to four alkyl substituents on themain chain, and a reducing agent, such as a hydrogen/palladium carboncatalyst. Alternatively, the N-alkylaspartyl dipeptide ester compound ofthe present invention can be produced by reductive alkylation of anaspartame compound, having a protecting group in a β-position in thecarboxylic acid, such as β-O-benzyl-α-L-aspartyl-L-amino acid methylester, using the above-described 3-phenylpropionaldehyde compound, acinnamaldehyde compound or a (2-phenylethyl) alkylketone compound, and areducing agent, such as NaB(OAc)₃H, as disclosed in A. F. Abdel-Magid etal., Tetrahedron letters, 31, 5595 (1990), followed by removal ofprotecting groups thereof, or by a method consisting in saturatingunsaturated bonds with a reducing agent, as the occasion may demand. Theabove aspartame compound may be obtained by a usual peptide synthesismethod, as discussed in Izumiya et al., Fundamentals and Experimentationin Peptide Synthesis. Published by MARUZEN on Jan. 20, 1985. The methodfor synthesis of the compounds in the present invention is, however, notlimited to these methods. In place of the above-mentioned3-phenylpropionaldehyde compound, cinnamaldehyde compound or the(2-phenylethyl) alkyl ketone compound, acetal or ketal compounds thereofmay, of course, be used as the aldehyde or ketone components at the timeof the reductive alkylation.

As a result of sensory evaluation, the present compounds and saltsthereof were found to have strong sweetening potency and have sensory(organoleptic) properties similar to that of sugar. For example, thesweetness ofN-[N-[3-(3-hydroxy-4-methoxyphenyl)-3-methylbutyl]-L-α-aspartyl]-L-phenylalanine1-methyl ester was approximately 70000 times that of sugar, thesweetness of N-[N-[3-(3-methyl-4hydroxyphenyl)-3-methylbutyl]-L-α-aspartyl]-L-phenylalanine 1-methylester was approximately 70000 times that of sugar, the sweetness ofN-[N-[3-(3-hydroxy-4-methylphenyl)-3-methylbutyl]-L-α-aspartyl]-L-phenylalanine 1-methyl ester was approximately 60000 timesthat of sugar, and the sweetness of N-[N-((RS)-3-(3hydroxy-4-methoxyphenyl) butyl]-L-α-aspartyl]-L-phenylalanine 1-methylester was approximately 50000 times that of sugar. On the other hand,the half life in a buffer of pH=3.0 at 72.0° C. ofN-[N-[3-(3-methoxy-4-hydroxyphenyl)-3-methylbutyl]-L-α-aspartyl]-L-phenylalanine1-methyl ester was 34.4 hours, which was substantially equivalent to thehalf life of N-[N-(3,3-dimethylbutyl)-L-α-aspartyl]-L-phenylalanine1-methyl ester (31.4 hours under the same condition). Also, the halflife in a buffer with pH=3.0 at 70.0° C. of aspartame,N-[N-(3,3-dimethylbutyl)-L-α-aspartyl)-L-phenylalanine 1-methyl ester,N-[N-[3-(3-hydroxy-4-methoxyphenyl)-3-methylbutyl]-L-α-aspartyl]-L-phenylalanine1- methyl ester andN-[N-(3-(4-hydroxyphenyl)-3-methylbutyl]-L-α-aspartyl)-L-phenylalanine1-methylester, was measured, and found to be 23.5, 38.3, 44.5 and 43.6hours, respectively. Sensory evaluations can be performed as describedin, for example, B. T. Carr, S. D. Pecore, K. M. Gibes and G. E. Dubois,“Sensory Methods for Sweetner Evaluation” in Flavor Measurement, editedby C. T. Ho and C. H. Manley, Marcel Decker, Inc. (1992).

The present application is a Continuation Application of PCT/JP99/04977filed Sep. 10, 1999 which claims priority to JP10-264252 filed Sep. 18,1998 and JP11-169419 filed Jun. 16, 1999. The contents of thesesdocuments are herein incorporated by reference into the presentspecification

Having generally described this invention, a further understanding canbe obtained by reference to certain specific examples which are providedherein for purposes of illustration only, and are not intended to belimiting unless otherwise specified.

EXAMPLES

In the following examples, the NMR spectra were measured using VarianGemini 300 (300 MHz) and MS spectra were measured using Thermo QuestTSQ700.

Example 1 Synthesis ofN-[N-[3-(3-hydroxy-4-methoxyphenyl)-3-methylbutyl]-L-α-aspartyl]-L-phenylalanine1-methyl ester (Table 1, compound number 10)

To 703 mg (1.45 mmol) ofN-t-butoxycarbonyl-β-o-benzyl-(α-L-aspartyl-L-phenylalanine methylester, 10 ml of a 4 N-HCl/dioxane solution were added and stirred atroom temperature for one hour. The reaction solution was concentratedunder reduced pressure. To the residue were added 50 ml of a 5%-aqueoussolution of sodium hydrogen carbonate and extraction was made twice with50 ml of ethyl acetate. An organic layer was washed with a saturatedsaline water and dried over anhydrous magnesium sulfate. Magnesiumsulfate was filtered off and the liquid filtrate was concentrated underreduced pressure to yield 557 mg (1.45 mmol) of(3-O-benzyl-(α-L-aspartyl-L-phenylalanine methyl ester, as a viscousoily substance.

557 mg (1.45 mmol) of the above β-O-benzyl-α-L-aspartyl-L-phenylalaninemethyl ester were dissolved in 15 ml of tetrahydrofuran (THF) to yield asolution which was maintained at 0° C. To this solution were added 432mg (1.45 mmol) of 3-(3-benzyloxy-4-methoxyphenyl)-3-methylbutylaldehyde, 0.083 ml (1.45 mmol) of acetic acid and 462 mg (2.18 mmol) ofNaB(OAc)₃H and stirred for one hour at 0 ° C. and overnight at roomtemperature. To the reaction solution were added 50 ml of a saturatedaqueous solution of sodium hydrogen carbonate and extraction was madetwice with 50 ml of ethyl acetate. An organic layer was washed with asaturated saline water and dried over anhydrous magnesium sulfate.Magnesium sulfate was filtered off and the liquid filtrate wasconcentrated under reduced pressure. The residue was purified withpreparative thin layer chromatography (PTLC) to yield 832 mg (1.25 mmol)ofN-[N-[3-(3-benzyloxy-4-methoxyphenyl)-3-methylbutyl]-(3-O-benzyl-L-α-aspartyl]-L-phenylalanine1-methylester as a viscous oily substance.

The above 832 mg (1.25 mmol) ofN-[N-[3-(3-benzyloxy-4-methoxyphenyl)-3-methylbutyl]-β-O-benzyl-L-α-aspartyl]-L-phenylalanine1-methyl ester were dissolved in a mixed solvent of 25 ml of methanoland 2 ml of water, and 350 mg of 10% palladium carbon (containing 50% ofwater) were added thereto. The resulting mixture was reduced at roomtemperature for three hours under a hydrogen atmosphere. The catalystwas filtered off and the filtrate was concentrated under reducedpressure. The residue was purified with PTLC to remove an odor adsorbedto yield 400 mg (0.82 mmol) ofN-[N-[3-(3-hydroxy-4-methoxyphenyl)-3-methylbutyl]-L-α-L-aspartyl)-L-phenylalanineL-methylester as a solid substance.

¹HMMR (DMSO-d₆) δ: 1.14 (s, 6H), 1.54-1.68 (m, 2H), 2.04-2.22 (m, 3H),2.24-2.34 (dd, 1H), 2.84-2.94 (dd, 1H), 3.00-3.08 (dd, 1H), 3.31-3.36(m, 1H), 3.59 (s, 3H), 3.71 (s, 3H), 4.46-4.55 (m, 1H), 6.60-6.65 (dd,1H), 6.73 (s, 1H), 6.80 (d, 1H), 7.10-7.28 (m, 5H), 8.45 (d, 1H), 8.75(brs, 1H). ESI (Electrospray Ionization)-MS 487.3 (MH⁺)

Sweetness (sweetening potency), 70000 times the sweetness of sugar

Example 2 Synthesis of N-[N-[3-(4-methoxyphenyl)-3-methylbutyl]-L-α-aspartyl)-L-phenylalanine1-methyl ester (Table 1, compound number 7)

N-[N-[3-(4-methoxyphenyl)-3-methylbutyl)-L-α-aspartyl)-L-phenylalanine1-methyl ester was obtained as a solid substance, with a total yield of72.2%, in the same way as in Example 1, except using3-(4-methoxyphenyl)-3-methylbutyl aldehyde in place of3-(3-benzyloxy-4-methoxyphenyl)-3-methylbutyl aldehyde.

¹HMMR (DMSO-d₆) δ: 1.17 (s, 6H), 1.62-1.72 (m, 2H), 2.04-2.20 (m, 3H),2.24-2.34 (dd, 1H), 2.84-2.94 (dd, 1H), 2.95-3.07 (dd, 1H), 3.30-3.35(m, 1H), 3.51 (s, 3H), 3.70 (s, 3H), 4.46-4.54 (m, 1H), 6.83 (d, 2H).7.14-7.28 (m, 7H), 8.43 (d, 1H). ESI-MS 471.3 (MH⁺)

Sweetness, 25000 times the sweetness of sugar

Example 3 Synthesis ofN-[N-[3-(4-hydroxyphenyl)-3-methylbutyl]-L-α-aspartyl]-L-phenylalanine 1methyl ester (Table 1, compound number 8)

N-[N-[3-(4-hydroxyphenyl)-3-methylbutyl]-L-α-aspartyl]-L-phenylalanine1-methyl ester was obtained as a solid substance, with a total yield of64.5%, in the same way as in Example 1, except using3-(4-benzyloxyphenyl)-3-methylbutyl aldehyde in place of3-(3-benzyloxy-4-methoxyphenyl)-3-methylbutyl aldehyde.

¹HMMR (DMSO-d₆) δ: 1.15 (s, 6H), 1.58-1.72 (m, 2H), 2.04-2.20 (m, 3H),2.24-2.34 (dd, 1H), 2.85-2.94 (dd, 1H), 3.00-3.08 (dd, 1H), 3.30-3.36(m, 1H), 3.59 (s, 3H), 4.46-4.55 (m, 1H), 6.67 (d, 2H), 7.07 (d, 2H),7.10-7.27 (m, 5 H), 8.44 (d, 1H), 9.15 (brs, 1H). ESI-MS 457.3 (MH⁺)

Sweetness, 25000 times the sweetness of sugar

Example 4 Synthesis ofN-[N-[3-(3-methoxy-4-hydroxyphenyl)-3-methylbutyl]-L-α-aspartyl)-L-phenylalanine1 methyl ester (Table 1, compound number 9)

N-[N-[3-(3-methoxy-4-hydroxyphenyl)-3-methylbutyl]-L(α-aspartyl]-L-phenylalanine1-methyl ester was obtained as a solid substance, with a total yield of62.2%, in the same way as in Example 1, except using3-(3-methoxy-4-benzyloxyphenyl)-3-methylbutyl aldehyde in place of3-(3-benzyloxy-4-methoxyphenyl)-3-methylbutyl aldehyde.

¹HMMR (DMSO-d₆) δ: 1.17 (s, 6H), 1.63-1.72 (m, 2H), 2.08-2.22 (m, 3H),2.25-2.33 (dd, 1H), 2.86-2.94 (dd, 1H), 3.00-3.08 (dd, 1H), 3.33-3.38(m, 1H), 3.59 (s, 3H), 3.75 (s, 3H), 3.47-3.55 (m, 1H), 6.67 (s, 2H),6.81 (s, 1H), 7.14-7.27 (m, 5H), 8.46 (d, 1H), 8.70 (brs, 1H). ESI-MS487.3 (MH⁺)

Sweetness, 40000 times the sweetness of sugar

Example 5 Synthesis ofN-[N-[3-(3-hydroxy-4-methoxyphenyl)-3-methylbutyl]-L-α-aspartyl]-L-((α-methyl)phenylalanine 1-methylester (Table 1, compound number 22)

N-(N-[3-(3-hydroxy-4-methoxyphenyl)-3-methylbutyl]-L-α-aspartyl]-L-(α-methyl)phenylalanine 1-methyl ester was obtained as a solid substance, with atotal yield of 77.2%, in the same way as in Example 1, except usingN-t-butoxycarbonyl-β-O-benzyl-(α-L-aspartyl-L-(α-methyl) phenylalaninemethyl ester in place of N-t-butoxycarbonyl-β-O-benzyl-α-L-aspartyl-L-phenylalanine methyl ester.

¹HMMR (DMSO-d₆) δ: 1.18 (s, 6H), 1.22 (s, 3H), 1.66-1.76 (m, 2H),2.18-238 (m, 4H), 3.00 (d, 1H), 3.19 (d, 1H), 3.36-3.42 (m, 1H), 3.49(s, 3H), 3.72 (s, 3H), 6.67 (dd, 1H), 6.74 (d, 1H), 6.80 (d, 1H),7.02-7.06 (m, 2H), 7.20-7.30 (m, 3H), 8.29 (brs, 1H), 8.75 (brs, 1H).ESI-MS 501.3 (MH⁺)

Sweetness, 40000 times the sweetness of sugar

Example 6 Synthesis ofN-[N-[3-(2-hydroxyphenyl)-3-methylbutyl]-L-α-aspartyl]-L-phenylalanine1-methyl ester (Table 1, compound number 13)

N-[N-[3-(2-hydroxyphenyl)-3-methylbutyl]-L-α-aspartyl]-L-phenylalanine1-methyl ester was obtained as a solid substance, with a total yield of64.5%, in the same way as in Example 1, except using3-(2-benzyloxyphenyl)-3-methylbutyl aldehyde in place of3-(3-benzyloxy-4-methoxyphenyl)-3-methylbutyl aldehyde.

¹HMMR (DMSO-d₆) δ: 1.26 (s, 6H), 1.84-2.30 (m, 6H), 2.88 (dd, 1H), 3.02(dd, 1H), 3.32-3.38 (m, 1H), 3.59 (s, 3H), 4.45-4.54 (m, 1H), 6.68-6.78(m, 3H), 6.96-7.06 (m, 2H), 7.12-7.30 (m, 5H), 8.50 (d, 1H), 9.30 (brs,1H). ESI-MS 457.4 (MH⁺)

Sweetness, 8000 times the sweetness of sugar

Example 7 Synthesis ofN-[N-[3-(2-hydroxy-4-methoxyphenyl)-3-methylbutyl]-L-α-aspartyl]-L-phenylalanine1-methyl ester (Table 1, compound number 14)

N-[N-[3-(2-hydroxy-4-methoxyphenyl)-3-methylbutyl]-L-α-aspartyl]-L-phenylalanine1-methyl ester was obtained as a solid substance, with a total yield of44.1%, in the same way as in Example 1, except using3-(2-benzyloxy-4-methoxyphenyl)-3-methylbutyl aldehyde in place of3-(3-benzyloxy-4-methoxy phenyl)-3-methylbutyl aldehyde.

¹HMMR (DMSO-d₆) δ: 1.22 (s, 6H), 1.82-2.20 (m, 5H), 2.26 (dd, 1H), 2.88(dd, 1H), 3.01 (dd, 1H), 3.34-3.40 (m, 1H), 3.59 (s, 3H), 3.64 (s, 3H),4.46-4.53 (m, 1H), 6.28 (dd, 1H), 6.36 (d, 1H), 6.92 (d, 1H), 7.14-7.26(m, 5H), 8.52 (d, 1H), 9.40 (brs, 1H). ESI-MS 487.3 (MH⁺)

Sweetness, 20000 times the sweetness of sugar

Example 8 Synthesis ofN-[N-[3-(2-hydroxy-4-methylphenyl)-3-methylbutyl]-L-α-aspartyl]-L-phenylalanine1-methyl ester (Table 1, compound number 15)

N-(N-[3-(2-hydroxy-4-methylphenyl)-3-methylbutyl]-L-α-aspartyl]-L-phenylalanine1-methyl ester was obtained as a solid substance, with a total yield of45.1%, in the same way as in Example 1, except using3-(2-benzyloxy-4-methylphenyl)-3-methylbutyl aldehyde in place of3-(3-benzyloxy-4-methoxyphenyl)-3-methylbutyl aldehyde.

¹HMMR (DMSO-d₆) δ: 1.23 (s, 6H), 1.82-2.20 (m, 5H), 2.14 (s, 3H), 2.25(dd, 1H), 2.88 (dd, 1H), 3.01 (dd, 1H), 3.33-3.39 (m, 1H), 3.58 (s, 3H),4.46-4.54 (m, 1H), 6.51 (d, 1H), 6.87 (s, 1H), 6.90 (d, 1H), 7.10-7.23(m, 5H), 8.51 (d, 1H), 9.20 (brs, 1H). ESI-MS 471.2 (MH⁺)

Sweetness, 25000 times the sweetness of sugar

Example 9 Synthesis ofN-[N-[3-(3,4-methylenedioxyphenyl)-3-methylbutyl]-L-α-aspartyl]-L-phenylalanine-1-methylester (Table 1, compound number 16)

N-[N-[3-(3,4-methylenedioxyphenyl)-3-methylbutyl]-L-α-aspartyl]-L-phenylalanine1-methyl ester was obtained as a solid substance, with a total yield of69.7%, in the same way as in Example 1, except using3-(3,4-methylenedioxy phenyl)-3-methylbutyl aldehyde in place of3-(3-benzyloxy-4-methoxyphenyl)-3-methylbutyl aldehyde.

¹HMMR (DMSO-d₆) δ: 1.16 (s, 6H), 1.60-1.70 (m, 2H), 2.05-2.20 (m, 3H),2.27 (dd, 1H), 2.89 (dd, 1H), 3.03 (dd, 1H), 3.31-3.35 (m, 1H), 3.59 (s,3H), 4.46-4.54 (m, 1H), 5.94 (s, 2H), 6.72 (dd, 1H), 6.79 (d, 1H), 6.88(d, 1H), 7.15-7.28 (m, 5H), 8.44 (d, 1H). ESI-MS 485.4 (MH⁺)

Sweetness, 30000 times the sweetness of sugar

Example 10 Synthesis ofN-[N-[3-(3-methyl-4-methoxyphenyl)-3-methylbutyl]-L-α-aspartyl]-L-phenylalanine1-methyl ester (Table 1, compound number 17)

N-[N-[3-(3-methyl-4-methoxyphenyl)-3-methylbutyl]-L-α-aspartyl]-L-phenylalanine1-methyl ester was obtained as a solid substance, with a total yield of66.0%, in the same way as in Example 1, except using3-(3-methyl-4-methoxyphenyl)-3-methylbutyl aldehyde in place of3-(3-benzyloxy-4-methoxy phenyl)-3-methylbutyl aldehyde. ¹HMMR (DMSO-d₆)δ: 1.16 (s, 6H), 1.63-1.72 (m, 2H), 2.13 (s, 3H), 2.08-2.20 (m, 3H),2.25-2.32 (dd, 1H), 2.85-2.95 (dd, 1H), 3.00-3.06 (dd, 1H), 3.31-3.36(m, 1H), 3.59 (s, 3H), 3.73 (s, 3H), 4.47-4.55 (m, 1H), 6.79-6.82 (m,1H), 7.03-7.06 (m, 2H), 7.15-7.27 (m, 5H), 8.44-8.47 (d, 1H). ESI-MS485.5 (MH⁺)

Sweetness, 30000 times the sweetness of sugar

Example 11 Synthesis ofN-[N-[3-(3-methyl-4-hydroxyphenyl)-3-methylbutyl)-L-α-aspartyl]-L-phenylalanine1-methyl ester (Table 1, compound number 18)

N-[N-[3-(3-methyl-4-hydroxyphenyl)-3-methylbutyl]-L-α-aspartyl]-L-phenylalanine1-methyl ester was obtained as a solid substance, with a total yield of63.2%, in the same way as in Example 1, except using3-(3-methyl-4-benzyloxyphenyl)-3-methylbutyl aldehyde in place of3-(3-benzyloxy-4-methoxyphenyl)-3-methylbutyl aldehyde.

¹HMMR (DMSO-d₆) δ: 1.14 (s, 6H), 1.59-1.68 (m, 2H), 2.09 (s, 3H),2.09-2.18 (m, 3H), 2.25 (dd, 1H), 2.90 (dd, 1H), 3.02 (dd, 1H),3.30-3.36 (m, 1H), 3.59 (s, 3H), 4.46-4.54 (m, 1H), 6.68 (d, 1H), 6.88(dd, 1H), 6.96 (s, 1H), 6.14-6.73 (m, 5H), 8.46 (d, 1H), 9.01 (brs, 1H).ESI-MS 471.4 (MH⁺)

Sweetness, 70000 times the sweetness of sugar

Example 12 Synthesis of N-[N-[2-[1-(3-methoxy-4-hydroxyphenyl)cyclopentyl]ethyl]-L-α-aspartyl]-L-phenylalanine 1-methyl ester (Table1, compound number 20)

N-[N-(2-[1-(3-methoxy-4-hydroxyphenyl)cyclopentyl]ethyl]-L-α-aspartyl]-L-phenylalanine 1-methyl ester wasobtained as a solid substance, with a total yield of 68.4%, in the sameway as in Example 1, except using 2-[1-(3-methoxy-4-hydroxyphenyl)cyclopentyl]acetaldehyde in place of3(3-benzyloxy-4-methoxyphenyl)-3-methylbutyl aldehyde.

¹HMMR (DMSO-d₆) δ: 1.48-1.82 (m, 10H), 2.00-2.16 (m, 3H), 2.24 (dd, 1H),2.90 (dd, 1H), 3.01 (dd, 1H), 3.30-3.40 (m, 1H), 3.59 (s, 3H), 3.74 (s,3H), 4.45-4.53 (m, 1H), 6.59 (dd, 1H), 6.65 (d, 1H), 6.75 (dd, 1H),7.14-7.28 (m, 5H), 8.44 (d, 1H), 8.70 (brs, 1H). ESI-MS 513.4 (MH⁺)

Sweetness, 30000 times the sweetness of sugar

Example 13 Synthesis ofN-[N-[3-(3-hydroxy-4-methoxyphenyl)-3-methylbutyl]-L-α-aspartyl]-L-phenylalanine1-ethyl ester (Table 1, compound number 21)

N-[N-[3-(3 -hydroxy-4-methoxyphenyl)-3-methylbutyl]-L-α-aspartyl]-L-phenylalanine 1-ethyl ester was obtainedas a solid substance, with a total yield of 56.1%, in the same way as inExample 1, except usingN-t-butoxycarbonyl-β-O-benzyl-α-L-aspartyl-L-phenylalanine ethyl esterin place of N-t-butoxycarbonyl-β-O-benzyl-α-L-aspartyl-L-phenylalaninemethyl ester.

¹HMMR (DMSO-d₆) δ: 1.09 1.13 (m, 9H), 1.58-1.67 (m, 2H), 2.08-2.37 (m,4H), 2.86-2.93 (dd, 1H), 2.99-3.06 (dd, 1H), 3.32-3.37 (m, 1H), 3.71 (s,3H), 4.00-4.07 (m, 2H), 4.44-4.51 (m, 1H), 6.62-6.65 (d, 1H), 6.74-6.81(m, 2H), 7.15-7.27 (m, 5H), 8.46 (d, 1H), 8.78 (brs, 1H) ESI-MS 501.3(MH⁺)

Sweetness, 15000 times the sweetness of sugar

Example 14 Synthesis of N-[N-[(RS)-3-(3-methoxy-4-hydroxyphenyl)butyl]-L-α-aspartyl]-L-phenylalanine 1-methyl ester (Table 1, compoundnumber 3)

419 mg (1.09 mmol) of β-O-benzyl-α-L-aspartyl-L-phenylalanine methylester, obtained in the same way as in Example 1, were dissolved in 10 mlof THF and the resulting solution was maintained at 0° C. To thissolution were added 308 mg (1.09 mmol) of3-β-methoxy-4-benyloxyphenyl)-2-butenal, 0.062 ml (1.09 mmol) of aceticacid and 345 mg (1.63 mmol) of NaB (OAc)₃H and the resulting mixture wasstirred at 0° C. for one hour and further stirred overnight at roomtemperature. To the reaction solution were added 30 ml of a saturatedaqueous solution of sodium hydrogen carbonate and extraction was carriedout twice with 30 ml of ethyl acetate. An organic layer was washed withsaturated saline water and dried over anhydrous magnesium sulfate. Afterfiltering magnesium sulfate off, the liquid filtrate was concentratedunder reduced pressure. The residue was purified with preparative thinlayer chromatography (PTLC) to obtain 534 mg (0.82 mmol) ofN-[N-[3-(3-methoxy-4-benzyloxyphenyl)2-butenyl]-β-O-benzyl-L-β-aspartyl]-L-phenylalanine1-methyl ester as a viscous oily substance.

534 mg (0.82 mmol) of the aboveN-[N-[3-(3-methoxy-4-benzyloxyphenyl-2-butenyl)-β-O-benzyl-L-αaspartyl]-L-phenylalanine1-methyl ester were dissolved in a mixed solvent of 20 ml of methanoland 1 ml of water. To the resulting mixture were added 200 mg of 10%palladium carbon (containing 50% of water). The resulting mixture wasreduced at room temperature for three hours in a hydrogen atmosphere.The catalyst was filtered off and the resulting filtrate wasconcentrated under reduced pressure. The residue was purified with PTLCto remove an odor adsorbed to obtain 269 mg (0.57 mmol) of N-[N-[(RS)-3-(3-methoxy-4-hydroxyphenyl) butyl]-L-α-aspartyl]-L-phenylalanine1-methyl ester as a solid substance.

¹HMMR (DMSO-d₆) δ: 1.10 (2d, 3H), 1.50-1.60 (m, 2H), 2.10-2.40 (m, 4H),2.55-2.65 (m, 1H), 2.81-2.95 (m, 1H), 3.03-3.09 (dd, 1H), 3.34-3.40 (m,1H), 3.60 (s, 1.5H), 3.61 (s, 1.5H), 3.74 (s, 1.5H), 3.75 (s, 1.5H),4.50-4.60 (m, 1H), 6.55 (d, 1H), 6.67 (d, 1H), 6.72 (s, 1H), 7.15-7.30(m, 5H), 8.50 (brd, 1H), 8.70 (brs, 1H). ESI-MS 473.3 (MH⁺)

Sweetness, 30000 times the sweetness of sugar

Example 15 Synthesis of N-[N-[(RS)-3-(4-methoxyphenyl)butyl]-L-α-aspartyl]-L-phenylalanine 1-methyl ester (Table 1, compoundnumber 1)

N-[N-[(RS)-3-(4-methoxyphenyl) butyl]-L-aspartyl]-L-phenylalanine1-methyl ester was obtained as a solid substance with a total yield of37.3% in the same way as in Example 14 except using3-(4-methoxyphenyl)-2-butenal in place of3-(3-methoxy-4-benzyloxyphenyl)-2-butenal.

¹HMMR (DMSO-d₆) δ: 1.09 (d, 1.5H), 1.11 (d, 1.5H), 1.54 (m, 2H),2.17-2.23 (m, 3H), 2.28-2.38 (m, 1H), 2.64 (m, 1H), 2.85-2.95 (m, 1H),3.02-3.10 (dd, 1H), 3.60 (s, 1.5H). 3.61 (s, 1.5H), 3.70 (s, 1H), 4.54(m, 1H), 6.83 (d, 2H), 7.07 (d, 2H), 7.18-7.28 (m, 5H). ESI-MS 457.3(MH⁺)

Sweetness, 16000 times the sweetness of sugar

Example 16 Synthesis of N-[N-[(RS)-3-(3-hydroxyphenyl)butyl]-L-α-aspartyl]-L-phenylalanine 1 methyl ester (Table 1, compoundnumber 2)

N-[N-[(RS)-3-(3-hydroxyphenyl) butyl]-L-α-aspartyl]-L-phenylalanine1-methyl ester was obtained as a solid substance with a total yield of31.1% in the same way as in Example 14 except using3-(3-benzyloxyphenyl)-2-butenal in place of3-(3-methoxy-4-benzyloxyphenyl)-2-butenal.

¹HMMR (DMSO-d₆) δ: 1.09 (m, 3H), 1.55 (m, 2H), 2.10-2.24 (m, 3H),2.26-2.34 (dd, 1H), 2.58 (m, 1H), 2.85-2.98 (m, 1H), 3.01-3.10 (dd, 1H),3.60 (s, 1.5H), 3.61 (s, 1.5H), 4.53 (m, 1H), 6.55-6.62 (m, 3H), 7.05(t, 1H), 7.16-7.30 (m, 5H), 8.47 (m, 1H ), 8.75 (brs, 1H). ESI-MS 443.2(MH⁺)

Sweetness, 12000 times the sweetness of sugar

Example 17 Synthesis of N-[N-[(RS)-3-(3-hydroxy-4-methoxyphenyl)butyl]-L-α-aspartyl]-L-phenylalanine 1-methyl ester (Table 1, compoundnumber 4)

N-[N-[(RS)-3-(3-hydroxy-4-methoxyphenyl)butyl]-L-α-aspartyl]-L-phenylalanine 1-methyl ester was obtained as asolid substance with a total yield of 38.8% in the same way as inExample 14 except using 3-(3-benzyloxy-4-methoxyphenyl)-2-butenal inplace of 3-(3-methoxy-4-benzyloxyphenyl)-2-butenal.

¹HMMR (DMSO-d₆) δ: 1.08 (m, 3H), 1.53 (m, 2H), 2.13-2.21 (m, 3H), 2.28(dd, 1H), 2.56 (m, 1H), 2.86-3.00 (m, 1H), 3.02-3.12 (dd, 1H), 3.29-3.40(m, 1H), 3.60 (s, 1.5H), 3.61 (s, 1.5H), 3.71 (s, 3H), 4.53 (m, 1H),6.53 (d, 1H), 6.60 (d, 1H), 6.79 (d, 1H), 7.15-7.26 (m, 5H), 8.46 (m,1H), 8.75 (brs, 1H). ESI-MS 473.3 (MH⁺)

Sweetness, 50000 times the sweetness of sugar

Example 18 Synthesis of N-[N-[3-(RS)-3-hydroxy-4-methoxyphenyl)butyl]-L-α-aspartyl]-3-cyclohexyl-L-alanine 1-methyl ester (Table 1,compound number 6)

N-[N-[(RS)-3-(3-hydroxy-4-methoxyphenyl)butyl]-L-α-aspartyl]-3-cyclohexyl-L-alanine 1-methyl ester was obtainedas a solid substance with a total yield of 41.7% in the same way as inExample 14 except usingN-t-butoxycarbonyl-β-O-benzyl-α-L-aspartyl-3-cyclohexyl-Lalanine methylester in place ofN-t-butoxycarbonyl-β-O-benzyl-α-L-aspartyl-L-phenylalanine methyl esterand also except using 3-(3-benzyloxy-4-methoxyphenyl)-2-butenal in placeof 3-(3-methoxy-4-benzyloxyphenyl)-2-butenal.

¹HMMR (DMSO-d₆) δ: 0.75-1.34 (m, 5H), 1.11 (d, 3H), 1.50-1.70 (m, 1H),2.18-2.28 (m, 2H), 2.35-2.45 (m, 2H), 2.58-2.65 (m, 1H), 3.27-3.36 (m,1H), 3.60 (m, 3H), 3.71 (s, 3H), 4.35 (m, 1H), 6.53-6.60 (m, 1H), 6.61(d, 1H), 6.79 (d, 1H), 8.44 (m, 1H), 8.80 (brs, 1H). ESI-MS 479.4 (MH⁺)

Sweetness, 40000 times the sweetness of sugar

Example 19 Synthesis of N-[N-[(RS)-3-(3-methoxy-4-hydroxyphenyl)butyl]-L-α-aspartyl]-L-tyrosine 1-methyl ester (Table 1, compound number5)

N-[N-[(RS)-3-(3-methoxy-4-hydroxyphenyl)-butyl]-L-α-aspartyl]-L-tyrosine1-methyl ester was obtained as a solid substance with a total yield of37.5% in the same way as in Example 14 except usingN-t-butoxycarbonyl-β-O-benzyl-α-L aspartyl-L-tyrosine methyl ester inplace of N-t-butoxycarbonyl-β-O-benzyl-α-L-aspartyl-L-phenylalaninemethyl ester.

¹HMMR (DMSO-d₆) δ: 1.10 (d, 3H), 1.55 (m, 2H), 2.16-2.41 (m, 4H), 2.58(m, 1H), 2.70-2.82 (m, 1H), 2.85-2.95 (dd, 1H), 3.58 (s, 3H), 3.78 (s,3H), 4.43 (m, 1H), 6.53-6.75 (m, 5H), 6.96 (d, 2H), 8.49 (brd, 1H), 8.75(brs, 1H), 9.80 (brs, 1H) ESI-MS 489.3 (MH⁺)

Sweetness, 25000 times the sweetness of sugar

Example 20 Synthesis of N-[N-[(RS)-3-(3-methyl-4-hydroxyphenyl)butyl]-L-α-aspartyl]-L-phenylalanine 1-methyl ester (Table 1, compoundnumber 11)

N-[N-[(RS)-3-(3-methyl-4-hydroxy phenyl)butyl]-L-α-aspartyl]-L-phenylalanine 1-methyl ester was obtained as asolid substance with a total yield of 19.7% in the same way as inExample 14 except using 3-(3-methyl-4-benzyloxyphenyl)-2-butenal inplace of 3-(3-methoxy-4-benzyloxyphenyl)-2-butenal.

¹HMMR (DMSO-d₆) δ: 1.06-1.09 (m, 3H), 1.49-1.54 (m, 2H), 2.08 (m, 3H),2.11-2.20 (m, 3H), 2.17-2.33 (m, 1H), 2.85-2.95 (m, 2H), 3.05-3.09 (m,1H), 3.33-3.37 (m, 1H), 3.61 (s, 3H), 4.50-4.55 (m, 1H), 6.65 (m, 1H),6.76 (m, 1H), 6.84 (s, 1H), 7.16-7.28 (m, 5H), 8.47-8.50 (m, 1H), 9.02(brs, 1H) ESI-MS 457.2 (MH⁺).

Sweetness, 50000 times the sweetness of sugar

Example 21 Synthesis ofN-[N-[3-(3-hydroxy-4-methoxyphenyl)-(RS)-2-methylpropyl)-L-α-aspartyl)-L-phenylalanine1-methyl ester (Table 1, compound number 12)

N-[N-[3-(3-hydroxy-4-methoxyphenyl)-(RS)-2-methylpropyl]-L-α-aspartyl]-L-phenylalanine1-methyl ester was obtained as a solid substance with a total yield of45.6% in the same way as in Example 14 except using3-(3-benzyloxy-4-methoxyphenyl)-2-methyl-2-propenal in place of3-(3-methoxy-4-benzyloxyphenyl)-2-butenal.

¹HMMR (DMSO-d₆) δ: 0.68-0.85 (m, 3H), 1.65-1.82 (m, 1H), 2.08-2.37 (m,2H), 2.27-2.30 (d, 4H), 2.94-3.10 (m, 2H), 3.43-3.45 (m, 1H), 3.62 (s,3H), 3.72 (s, 3H), 4.48-4.59 (m, 1H), 6.49-6.59 (m, 2H), 6.77-6.80 (m,1H), 7.20-7.29 (m, 5H), 8.57-8.58 (m, 1H), 8.92 (brs, 1H). ESI-MS 473.4(MH⁺)

Sweetness, 5000 times the sweetness of sugar

Example 22 Synthesis ofN-[N-[3-(3-hydroxy-4-methylphenyl)-3-methylbutyl]-L-α-aspartyl]-L-phenylalanine1-methyl ester (Table 1, compound number 19)

274 mg (0.97 mmol) of 3-[(3-benzyloxy-4-methyl) phenyl]-3-methylbutylaldehyde, 353 mg (1.2 mmol) of aspartame and 100 mg of 10% palladiumcarbon (containing 50% of water) were added to 7 ml of methanol andstirred at room temperature for four hours in a hydrogen atmosphere. Thecatalyst was filtered off and the resulting filtrate was concentratedunder reduced pressure. The residue was purified by preparative thinlayer chromatography (PTLC) to produce 299 mg (0.64 mmol, 65.5) ofN-[N-[3-(3-hydroxy-4-methylphenyl)-3-mehylbutyl]-L-α-aspartyl]-L-phenylalanine1-methyl ester as a solid substance.

¹HMMR (DMSO-d₆) δ: 1.14 (s, 6H), 1.58-1.70 (m, 2H), 2.05 (s, 3H),2.07-242 (m, 4 H), 2.89 (dd, 1H), 3.03 (dd, 1H), 3.30-3.40 (m, 1H), 3.59(s, 3H), 4.46-4.54 (m, 1H), 6.60 (d, 1H), 6.73 (s, 1H), 6.94 (d, 1H),7.15-7.30 (m, 5H), 8.46 (brs, 1H) 9.08 (brs, 1H). ESI-MS 471.3 (MH⁺)

Sweetness, 60000 times the sweetness of sugar

Example 23 Synthesis ofN-[N-[3-(3,4-dihydroxyphenyl)-3-mehylbutyl]-L-α-aspartyl]-L-phenylalanine1-methyl ester (Table 1, compound number 23)

N-[N-[3-(3,4-dihydroxyphenyl)-3-methylbutyl]-L-α-aspartyl]-L-phenylalanine1-methyl ester was obtained as a solid substance with a total yield of76.5% in the same way as in Example 1 except using3-(3,4-dibenzyloxyphenyl)-3methylbutyl aldehide in place of3-(3-benzyloxy-4-methoxyphenyl)-3-methlbutyl aldehide.

¹HMMR (DMSO-d₆) δ: 1.14 (s, 6H), 1.76-1.93 (m, 2H), 2.40-2.50 (m, 2H),2.73-2.80 (m, 2H), 2.91 (dd, 1H), 3.06 (dd, 1H), 3.59 (s, 3H), 3.95-4.05(m, 1H) 4.45-4.55 (m, 1H), 6.52 (d, 1H), 6.64-6.70 (m, 2H), 6.94 (d,1H), 7.15-7.30 (m, 5H), 8.73 (brs, 1H), 8.80 (brs, 1H), 9.09 (brs, 1H).ESI-MS 473.3 (MW)

Sweetness, 50000 times the sweetness of sugar

Table 1 shows the structures of several synthesized N-alkyl aspartyldipeptide ester compounds, shown by the general formula (6) andsummarizes the results of the sensory evaluation tests.

As is shown by the results in Table 1, the novel compounds of thepresent invention are particularly excellent in sweetness (sweeteningpotency).

Structure of N-alkylasparatyl Dipeptide Ester Compound and SweetnessPotency

TABLE 1 Compound sweetness No. R₁ R₂ R₃ R₆ R₇ R₈ R₁₁ R₁₂ R₁₃ potency*¹ 1 H H OCH₃ CH₃ H H CH₂C₆H₅ H CH₃ 16000  2 H OH H CH₃ H H CH₂C₆H₅ H CH₃12000  3 H OCH₃ OH CH₃ H H CH₂C₆H₅ H CH₃ 30000  4 H OH OCH₃ CH₃ H HCH₂C₆H₅ H CH₃ 50000  5 H OCH₃ OH CH₃ H H CH₂C₆H₄-p-OH H CH₃ 25000  6 HOH OCH₃ CH₃ H H CH₂C₆H11 H CH₃ 40000  7 H H OCH₃ CH₃ CH₃ H CH₂C₆H₅ H CH₃25000  8 H H OH CH₃ CH₃ H CH₂C₆H₅ H CH₃ 25000  9 H OCH₃ OH CH₃ CH₃ HCH₂C₆H₅ H CH₃ 40000 10 H OH OCH₃ CH₃ CH₃ H CH₂C₆H₅ H CH₃ 70000 11 H CH₃OH CH₃ H H CH₂C₆H₅ H CH₃ 50000 12 H OH OCH₃ H H CH₃ CH₂C₆H₅ H CH₃ 500013 OH H H CH₃ CH₃ H CH₂C₆H₅ H CH₃ 8000 14 OH H OCH₃ CH₃ CH₃ H CH₂C₆H₅ HCH₃ 20000 15 OH H CH₃ CH₃ CH₃ H CH₂C₆H₅ H CH₃ 25000 16 H OCH₂O CH₃ CH₃ HCH₂C₆H₅ H CH₃ 30000 17 H CH₃ OCH₃ CH₃ CH₃ H CH₂C₆H₅ H CH₃ 30000 18 H CH₃OH CH₃ CH₃ H CH₂C₆H₅ H CH₃ 70000 19 H OH CH₃ CH₃ CH₃ H CH₂C₆H₅ H CH₃60000 20 H OCH₃ OH CH₂CH₂CH₂ CH₂ H CH₂C₆H₅ H CH₃ 30000 21 H OH OCH₃ CH₃CH₃ H CH₂C₆H₅ H CH₂CH₃ 15000 22 H OH OCH₃ CH₃ CH₃ H CH₂C₆H₅ CH₃ CH₃40000 23 H OH OH CH₃ CH₃ H CH₂C₆H₅ H CH₃ 50000 *¹values compared tosweetening potency of a 4% aqueous solution of sucrose

Effect of Invention

The novel N-alkylaspartyl dipeptide ester compound according to thepresent invention is low in calories and exhibits a sweetening potencywhich is particularly superior in comparison with conventionalsweetening agents. In the present invention, a novel chemical substancewhich has superior properties as a sweetening agent can be provided. Thenovel compound can be used not only for a sweetening agent but also forthe affording of sweetness to foods or the like products, such asbeverages (drinks) and foods, requiring sweet taste.

Obviously, numerous modifications and variations on the presentinvention are possible in light of the above teachings. It is thereforeto be understood that within the scope of the appended claims, theinvention may be practiced otherwise than as specifically describedherein.

1. An N-alkylaspartyl dipeptide ester compound, and salts thereof,represented by the formula (1):

wherein R₁, R₂, R₃, R₄ and R₅ are independent from each other, selectedfrom the group consisting of a hydrogen atom, a hydroxyl group, analkoxy group having 1 to 3 carbon atoms, an alkyl group having 1 to 3carbon atoms and a hydroxy alkyloxy group having two or three carbonatoms, and R₁ and R₂, or R₂ and R₃, optionally, form a methylene dioxygroup, and R₄ and R₅, and R₁ or R₃ which do not form the methylene dioxygroup are defined as above; R₆, R₇, R₈, R₉ and R₁₀ are independent fromeach other, a hydrogen atom or an alkyl group with 1 to 3 carbon atoms;and optionally, two of R₆, R₇, R₈, R₉ and R₁₀ may combine to form analkylene group with 1 to 5 carbon atoms, and R₆, R₇, R₈, R₉ and R₁₀which do not form the alkylene group with 1 to 5 carbon atoms aredefined as above; R₁₁ is selected from the group consisting of ahydrogen atom, a benzyl group, a p-hydroxy benzyl group, a cyclohexylmethyl group, a phenyl group, a cyclohexyl group, a phenyl ethyl groupand a cyclohexyl ethyl group; R₁₂ is selected from the group consistingof a hydrogen atom and an alkyl group with 1 to 3 carbon atoms; and R₁₃is selected from the group consisting of alkyl groups with 1 to 4 carbonatoms; with the proviso that the following are excluded: where R₆, R₇,R₈, R₉ and R₁₀ are hydrogen atoms at the same time, where R₆ is a methylgroup, R₁, R₂, R₃, R₄, R₅, R₇, R₈, R₉, R₁₀ and R₁₂ are a hydrogen atomat the same time and R₁₁ is a benzyl group or a p-hydroxy benzyl group,at the same time; and where R₂ or R₄ is a methoxy group, R₃ is ahydroxyl group, R₁₀ is a methyl group, R₁, R₄ or R₂, R₅, R₆, R₇, R₈ andR₉ are hydrogen atoms at the same time, and R₁₁ is a benzyl group or ap-hydroxy benzyl group.
 2. The compound as defined in claim 1, whereinR₃ is a methoxy group, R₁, R₂, R₃, R₄, R₅, R₇, R₈, R₉, R₁₀ and R₁₂ arehydrogen atoms, R₆ and R₁₃ are methyl groups and R₁₁ is a benzyl group.3. The compound as defined in claim 1, wherein R₂ is a hydroxyl group,R₁, R₃, R₄, R₅, R₇, R₈, R₉, R₁₀ and R₁₂ are hydrogen atoms, R₆ and R₁₃are methyl groups, and R₁₁ is a benzyl group.
 4. The compound as definedin claim 1, wherein R₂ is a methoxy group, R₃ is a hydroxyl group, R₁,R₄, R₅, R₇, R₈, R₉, R₁₀ and R₁₂ are hydrogen atoms, R₆ and R₁₃ aremethyl groups and R₁₁ is a benzyl group.
 5. The compound as defined inclaim 1, wherein R₂ is a hydroxyl group, R₃ is a methoxy group, R₁, R₄,R₅, R₇, R₈, R₉, R₁₀ and R₁₂ are hydrogen atoms, R₆ and R₁₃ are methylgroups and R₁₁ is a benzyl group.
 6. The compound as defined in claim 1,wherein R₂ is a methoxyl group, R₃ is a hydroxy group, R₁, R₄, R₅, R₇,R₈, R₉, R₁₀ and R₁₃ are hydrogen atoms, R₆ and R₁₃ are methyl groups andR₁₁ is a p-hydroxy benzyl group.
 7. The compound as defined in claim 1,wherein R₂ is a hydroxyl group, R₃ is a methoxy group, R₁, R₄, R₅, R₇,R₈, R₉, R₁₀ and R₁₃ are hydrogen atoms, R₆ and R₁₃ are methyl groups andR₁₁ is a cyclohexyl methyl group.
 8. The compound as defined in claim 1,wherein R₃ is a methoxy group, R₁, R₂, R₄, R₅, R₈, R₉, R₁₀ and R₁₂ arehydrogen atoms, R₆, R₇ and R₁₃ are methyl groups, and R₁₁ is a benzylgroup.
 9. The compound as defined in claim 1, wherein R₃ is a hydroxylgroup, R₁, R₂, R₄, R₅, R₈, R₉, R₁₀ and R₁₂ are hydrogen atoms, R₆, R₇and R₁₃ are methyl groups, and R₁₁ is a benzyl group.
 10. The compoundas defined in claim 1, wherein R₂ is a methoxy group, R₃ is a hydroxylgroup, R₁, R₄, R₅, R₈, R₉, R₁₀ and R₁₂ are hydrogen atoms, R₆, R₇ andR₁₃ are methyl groups, and R₁₁ is a benzyl group.
 11. The compound asdefined in claim 1, wherein R₂ is a hydroxyl group, R₃ is a methoxygroup, R₁, R₄, R₅, R₈, R₉, R₁₀ and R₁₂ are hydrogen atoms, R₆, R₇ andR₁₃ are methyl groups, and R₁₁ is a benzyl group.
 12. The compound asdefined in claim 1, wherein R₂ is a methyl group, R₃ is a hydroxylgroup, R₁, R₄, R₅, R₇, R₈, R₉, R₁₀ and R₁₂ are hydrogen atoms, R₆ andR₁₃ are methyl groups, and R₁₁ is a benzyl group.
 13. The compound asdefined in claim 1, wherein R₂ is a hydroxyl group, R₃ is a methoxygroup, R₁, R₄, R₅, R₆, R₇, R₉, R₁₀ and R₁₂ are hydrogen atoms R₈ and R₁₃are methyl groups, and R₁₁ is a benzyl group.
 14. The compound asdefined in claim 1, wherein R₁ is a hydroxyl group, R₂, R₃, R₄, R₅, R₈,R₉, R₁₀ and R₁₂ are hydrogen atoms, R₆, R₇ and R₁₃ are methyl groups,and R₁₁ is a benzyl group.
 15. The compound as defined in claim 1,wherein R₁ is a hydroxyl group, R₃ is a methoxy group, R₂, R₄, R₅, R₈,R₉, R₁₀ and R₁₂ are hydrogen atoms, R₆, R₇ and R₁₃ are methyl groups,and R₁₁ is a benzyl group.
 16. The compound as defined in claim 1,wherein R₁ is a hydroxyl group, R₃ is a methyl group, R₂, R₄, R₅, R₈,R₉, R₁₀ and R₁₂ are hydrogen atoms, R₆, R₇ and R₁₃ are methyl groups,and R₁₁ is a benzyl group.
 17. The compound as defined in claim 1,wherein R₂ and R₃ combine to form a methylene dioxy group, R₁, R₄, R₅,R₈, R₉, R₁₀ and R₁₂ are hydrogen atoms, R₆, R₇ and R₁₃ are methylgroups, and R₁₁ is a benzyl group.
 18. The compound as defined in claim1, wherein R₂ is a methyl group, R₃ is a methoxy group, R₁, R₄, R₅, R₈,R₉, R₁₀ and R₁₂ are hydrogen atoms, R₆, R₇, and R₁₃ are methyl groups,and R₁₁ is a benzyl group.
 19. The compound as defined in claim 1,wherein R₂ is a methyl group, R₃ is a hydroxyl group, R₁, R₄, R₅, R₈,R₉, R₁₀ and R₁₂ are hydrogen atoms, R₆, R₇ and R₁₃ are methyl groups,and R₁₁ is a benzyl group.
 20. The compound as defined in claim 1,wherein R₂ is a hydroxyl group, R₃ is a methyl group, R₁, R₄, R₅, R₈,R₉, R₁₀ and R₁₂ are hydrogen atoms, R₆, R₇ and R₁₃ are methyl groups,and R₁₁ is a benzyl group.
 21. The compound as defined in claim 1,wherein R₂ is a methoxy group, R₃ is a hydroxyl group, R₁, R₄, R₅, R₈,R₉, R₁₀ and R₁₂ are hydrogen atoms, R₆ and R₇ combine to form atetramethylene group, R₁₁ is a benzyl group, and R₁₃ is a methyl group.22. The compound as defined in claim 1, wherein R₂ is a hydroxyl group,R₃ is a methoxy group, R₁, R₄, R₅, R₈, R₉, R₁₀ and R₁₂ are hydrogenatoms, R₆ and R₇ are methyl groups, R₁₁ is a benzyl group, and R₁₃ is anethyl group.
 23. The compound as defined in claim 1, wherein R₂ is ahydroxyl group, R₃ is a methoxy group, R₁, R₄, R₅, R₈, R₉ and R₁₀ arehydrogen atoms, R₆, R₇, R₁₂ and R₁₃ are methyl groups, and R₁₁ is abenzyl group.
 24. The compound as defined in claim 1, wherein R₂ and R₃is a hydroxyl group, R₁, R₄, R₅, R₈, R₉, R₁₀ and R₁₂ are hydrogen atoms,R₆, R₇ and R₁₃ are methyl groups, and R₁₁ is a benzyl group.
 25. Thecompound as defined in claim 1, wherein when R₆ and R₇ differ, thecarbon atom to which R₆ is linked in said formula is in the (R), (S) or(RS) configuration.
 26. The compound as defined in claim 1, wherein whenR₈ and R₉ differ, the carbon atom to which R₈ is linked is in the (R),(S) or (RS) configuration.
 27. The compound as defined in claim 13,wherein when R₈ and R₉ differ the carbon atom to which R₈ is linked isin the (R), (S) or (RS) configuration.
 28. The compound as defined inclaim 1, wherein when R₁₀ is a substituent other than a hydrogen atom,the configuration of the carbon atom to which R₁₀ is linked in saidformula (1) is in the (R), (S) or (RS) configuration.
 29. A compositioncomprising at least one compound of claim 1 and a carrier or bulkingagent.
 30. A method of imparting sweetness into a substance comprisingadding at least one compound of claim 1 to said substance, wherein saidsubstance is selected from the group consisting of a food item, abeverage, a soft-drink, a fruit juice, a tea, water, a confectionery,chewing gum, a hygiene product, a toiletry, a cosmetic, a pharmaceuticalproduct and a veterinary product.
 31. A method of producing the compoundas defined in claim 1, wherein R₁₀ is a hydrogen atom comprising:reacting under reductive alkylation conditions an aldehyde having theformula (2):

 wherein R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₈ and R₉ have the same meanings asR₁, R₂, R₃, R₄ , R₅, R₆, R₇, R₈ and R₉, respectively in the aboveformula (1), with en aspartame compound having the formula (3):

 wherein R₁₁, R₁₂ and R₁₃ in formula (3) have the same meanings as R₁₁,R₁₂ and R₁₃ in formula (1), R₁₄ is a hydrogen atom or a substituentwhich can be converted into a hydrogen atom and R₁₅ is a hydrogen atom,benzyl group or a substituent which may be used to protect a carboxylgroup.
 32. The method as defined in claim 1, wherein R₁₅ is a t-butylgroup.
 33. A method of producing the compound as defined in claim 1,wherein R₇, R₉ and R₁₀ are a hydrogen atom comprising: reacting underreductive alkylation conditions an aldehyde having the formula (4):

 with an aspartame compound having the formula (3):

 wherein R₁₁, R₁₂ and R₁₃ in formula (3) have the same meanings as R₁₁,R₁₂ and R₁₃ in formula (1), R₁₄ is a hydrogen atom or a substituentwhich can be converted into a hydrogen atom and R₁₅ is a hydrogen atom,benzyl group or a substituent which may be used to protect a carboxylgroup.
 34. A method of producing the compound as defined in claim 1,comprising: reacting under reductive alkylation conditions an aldehydehaving the formula (5):

 wherein R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₈, R₉ and R₁₀ have the samemeanings as R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₈, R₉ and R₁₀, respectively informula (1); with an aspartame compound having the formula (3):

 wherein R₁₁, R₁₂ and R₁₃ in formula (3) have the same meanings as R₁₁,R₁₂ and R₁₃ in formula (1), R₁₄ is a hydrogen atom or a substituentwhich can be converted into a hydrogen atom and R₁₅ is a hydrogen atom,benzyl group or a substituent which may be used to protect a carboxylgroup.
 35. The composition according to claim 29, wherein said carrieror bulking agent is one or more compounds selected from the groupconsisting of polydextrose, starch, maltodextrines, cellulose,methylcellulose, carboxymethylcellulose and other cellulose compounds,sodium alginate, pectins, gums, lactose, maltose, glucose, sucrose,leucine, glycerole, mannitol, sorbitol, xylitol, and erythritol.
 36. Themethod of claim 34, wherein R₃ is a methoxy group, R₁, R₂, R₃, R₄, R₅,R₇, R₈, R₉, R₁₀ and R₁₂ are hydrogen atoms, R₆ and R₁₃ are methyl groupsand R₁₁ is a benzyl group.
 37. The method of claim 34, wherein R₂ is ahydroxyl group, R₁, R₃, R₄, R₅, R₇, R₈, R₉, R₁₀ and R₁₂ are hydrogenatoms, R₆ and R₁₃ are methyl groups, and R₁₁ is a benzyl group.
 38. Themethod of claim 34, wherein R₂ is a methoxy group, R₃ is a hydroxylgroup, R₁, R₄, R₅, R₇, R₈, R₉, R₁₀ and R₁₂ are hydrogen atoms, R₆ andR₁₃ are methyl groups and R₁₁ is a benzyl group.
 39. The method of claim34, wherein R₂ is a hydroxyl group, R₃ is a methoxy group, R₁, R₄, R₅,R₇, R₈, R₉, R₁₀ and R₁₂ are hydrogen atoms, R₆ and R₁₃ are methyl groupsand R₁₁ is a benzyl group.
 40. The method of claim 34, wherein R₂ is amethoxyl group, R₃ is a methoxy group, R₁, R₄, R₅, R₇, R₈, R₉, R₁₀ andR₁₂ are hydrogen atoms, R₆ and R₁₃ are methyl groups and R₁₁ is ap-hydroxy benzyl group.
 41. The method of claim 34, wherein R₂ is ahydroxyl group, R₃ is a methoxy group, R₁, R₄, R₅, R₇, R₈, R₉, R₁₀ andR₁₂ are hydrogen atoms, R₆ and R₁₃ are methyl groups and R₁₁ is acyclohexyl methyl group.
 42. The method of claim 34, wherein R₃ is amethoxy groups, R₁, R₂, R₄, R₅, R₈, R₉, R₁₀ and R₁₂ are hydrogen atoms,R₆, R₇ and R₁₃ are methyl groups, and R₁₁ is a benzyl group.
 43. Themethod of claim 34, wherein R₃ is a hydroxyl groups, R₁, R₂, R₄, R₅, R₈,R₉, R₁₀ and R₁₂ are hydrogen atoms, R₆, R₇ and R₁₃ are methyl groups,and R₁₁ is a benzyl group.
 44. The method of claim 34, wherein R₂ is amethoxy group, R₃ is a hydroxyl group, R₁, R₄, R₅, R₈, R₉, R₁₀ and R₁₂are hydrogen atoms, R₆, R₇ and R₁₃ are methyl groups, and R₁₁ is abenzyl group.
 45. The method of claim 34, wherein R₂ is a hydroxylgroup, R₃ is a hydroxyl group, R₁, R₄, R₅, R₈, R₉, R₁₀ and R₁₂ arehydrogen atoms, R₆, R₇ and R₁₃ are methyl groups, and R₁₁ is a benzylgroup.
 46. The method of claim 34, wherein R₂ is a methyl group, R₃ is ahydroxyl group, R₁, R₄, R₅, R₇, R₈, R₉, R₁₀ and R₁₂ are hydrogen atoms,R₆ and R₁₃ are methyl groups, and R₁₁ is a benzyl group.
 47. The methodof claim 34, wherein R₂ is a hydroxyl group, R₃ is a methoxy group, R₁,R₄, R₅, R₆, R₇, R₉, R₁₀ and R₁₂ are hydrogen atoms, R₈ and R₁₃ aremethyl groups, and R₁₁ is a benzyl group.
 48. The method of claim 34,wherein R₁ is a hydroxyl group, R₂, R₃, R₄, R₅, R₈, R₉, R₁₀ and R₁₂ arehydrogen atoms, R₆, R₇ and R₁₃ are methyl groups, and R₁₁ is a benzylgroup.
 49. The method of claim 34, wherein R₁ is a hydroxyl group, R₃ isa methoxy group, R₂, R₄, R₅, R₈, R₉, R₁₀ and R₁₂ are hydrogen atoms, R₆,R₇ and R₁₃ are methyl groups, and R₁₁ is a benzyl group.
 50. The methodof claim 34, wherein R₁ is a hydroxyl group, R₃ is a methyl group, R₂,R₄, R₅, R₈, R₉, R₁₀ and R₁₂ are hydrogen atoms, R₆, R₇ and R₁₃ aremethyl groups, and R₁₁ is a benzyl group.
 51. The method of claim 34,wherein R₂ and R₃ combine to form a methylene dioxy group, R₁, R₄, R₅,R₈, R₉, R₁₀ and R₁₂ are hydrogen atoms, R₆, R₇ and R₁₃ are methylgroups, and R₁₁ is a benzyl group.
 52. The method of claim 34, whereinR₂ is a methyl group, R₃ is a methoxy group, R₁, R₄, R₅,R₈, R₉, R₁₀ andR₁₂ are hydrogen atoms, R₆, R₇, and R₁₃ are methyl groups, and R₁₁ is abenzyl group.
 53. The method of claim 34, wherein R₂ is a methyl group,R₃ is a hydroxyl group, R₁, R₄, R₅,R₈, R₉, R₁₀ and R₁₂ are hydrogenatoms, R₆, R₇, and R₁₃ are methyl groups, and R₁₁ is a benzyl group. 54.The method of claim 34, wherein R₂ is a hydroxyl group, R₃ is a methoxygroup, R₁, R₄, R₅,R₈, R₉, R₁₀ and R₁₂ are hydrogen atoms, R₆, R₇, andR₁₃ are methyl groups, and R₁₁ is a benzyl group.
 55. The method ofclaim 34, wherein R₂ is a methoxy group, R₃ is a hydroxy group, R₁, R₄,R₅,R₈, R₉, R₁₀ and R₁₂ are hydrogen atoms, R₆, R₇ combine to form atetramethylene group, R₁₁ is a benzyl group, and R₁₃ is a methyl group.56. The method of claim 34, wherein R₂ is a hydroxyl group, R₃ is amethoxy group, R₁, R₄, R₅, R₈, R₉, R₁₀ and R₁₂ are hydrogen atoms, R₆and R₇ are methyl groups, R₁₁ is a benzyl group, and R₁₃ is an ethylgroup.
 57. The method of claim 34, wherein R₂ is a hydroxyl group, R₃ isa methoxy group, R₁, R₄, R₅,R₈, R₉ and R₁₀ are hydrogen atoms, R₆, R₇,R₁₂ and R₁₃ are methyl groups, and R₁₁ is a benzyl group.
 58. The methodof claim 34, wherein R₂ and R₃ are hydroxyl groups, R₁, R₄, R₅, R₈, R₉,R₁₀ and R₁₂ are hydrogen atoms, R₆, R₇ and R₁₃ are methyl groups, andR₁₁ is a benzyl group.
 59. The method of claim 34, wherein when R₆ andR₇ differ, the carbon atom to which R₆ is linked in said formula is inthe (R), (S) or (RS) configuration.
 60. The method of claim 34, whereinwhen R₈ and R₉ differ, the carbon atom to which R₈ is linked is in the(R), (S) or (RS) configuration.
 61. The method of claim 47, wherein whenR₈ and R₉ differ, the carbon atom to which R₈ is linked is in the (R),(S) or (RS) configuration.
 62. The method of claim 34, wherein when R₁₀is a substituent other than a hydrogen atom, the configuration of thecarbon atom to which R₁₀ is linked in said formula (1) is in the (R),(S) or (RS) configuration.